Tobacco smoking increases the risk of chronic pulmonary inflammation and lung cancer development. Much effort has been placed on identification of chemical carcinogens in tobacco smoke and monitoring their presence in smokers. However, not all smokers who are exposed to equivalent amounts of such carcinogens develop cancer. There is also a great variation in latency of lung cancer between individuals that do develop the disease. This suggests the existence of additional factors that contribute to the etiology of lung cancer. While genetic factors are likely to be of importance, based on our recent work showing a critical role for inflammation in other types of chemically-induced cancers, we propose that pulmonary inflammation is an important contributor to the pathogenesis of lung cancer. Pulmonary inflammation may also accelerate the metastatic spread of lung cancer, thereby making more than one contribution to the lethal nature of this disease. We propose that activation of the anti-apoptotic transcription factor NF-?B provides a link between chronic pulmonary inflammation caused by repetitive exposure to tobacco smoke and development and progression of lung cancer. We will use a conditional disruption of the gene encoding IKK[unreadable], a catalytic subunit of the I?B kinase (IKK) complex required for NF-?B activation, to determine the role of IKK[unreadable]-dependent NF-?B signaling in experimental lung carcinogenesis based on combined exposure to a chemical carcinogen and tobacco smoke. We will also use a conditional IKK[unreadable] deletion in myeloid cells to determine the contribution of NF-?B-driven inflammatory activation of cells such as alveolar macrophages to lung cancer development and progression. To circumvent the low efficiency of lung cancer induction by chemical carcinogens and its strong dependence on a particular genetic background we will also use transgenic models in which lung cancer is initiated by expression of K-ras or Raf-1 and will examine whether development and progression of these tumors is accelerated by tobacco smoke inhalation and other forms of pulmonary inflammation. In addition, we will use an experimental metastasis model based on orthotopic injections of Lewis lung carcinoma (LLC) cells to examine the contribution of inflammatory processes triggered either by exposure to tobacco smoke or by rapidly growing lung tumors to the metastatic spread of lung cancer. We will place special emphasis on the role of the innate immune system in the metastatic process and compare its activation by tobacco smoke inhalation to its activation by factors released by lung cancer cells. The proposed studies will provide critical and much needed information regarding the role of inflammation in lung carcinogenesis and tumor progression and should lay the foundation for anti-inflammatory therapy in prevention and treatment of lung cancer, the most prevalent cause of cancer-related mortality worldwide.